Long non-coding RNA MIR4300HG polymorphisms are associated with postoperative nausea and vomiting: a genome-wide association study.

BACKGROUND: Genetic factors such as single-nucleotide polymorphisms (SNPs) play a key role in the development of postoperative nausea and vomiting (PONV). However, previous findings are not widely applicable to different populations because of population-specific genetic variation. We developed a Japanese-specific DNA microarray for high-throughput genotyping. The aim of the current study was to identify SNPs associated with PONV on a genome-wide scale using this microarray in a sample of Japanese surgical patients. METHODS: Associations between 659,636 SNPs and the incidence of PONV 24 h after surgery in a limited sample of 24 female patients were assessed using the microarray. After imputation of genotypes at 24,330,529 SNPs, 78 SNPs were found to be associated with the incidence of PONV. We chose 4 of the 78 SNPs to focus on by in silico functional annotation. Finally, we genotyped these 4 candidate SNPs in 255 patients using real-time PCR to verify association with the incidence of PONV. RESULTS: The T > C variant of rs11232965 in the long non-coding RNA MIR4300HG was significantly associated with reduced incidence of PONV among genotypes and between alleles (p = 0.01 and 0.007). CONCLUSIONS: We identified a novel SNP (rs11232965) in the long non-coding RNA MIR4300HG that is associated with PONV. The rs11232965-SNP variant (T > C) is protective against the incidence of PONV. TRIAL REGISTRATION: This study was registered at the UMIN Clinical Trials Registry (Identifier: UMIN000022903 , date of registration: June 27, 2016, retrospectively registered.

Association of µ-opioid receptor gene (OPRM1) haplotypes with postoperative nausea and vomiting.

Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the µ-opioid receptor gene (OPRM1) might be associated with individual differences in opioid sensitivity, as well as with the incidence and severity of postoperative nausea and vomiting (PONV). The goal of the present study was to determine, in a cohort of Japanese surgical patients, genotypes and haplotypes of several SNPs in the OPRM1 gene, and their association with PONV during the early (first 24 h) postoperative period. We examined the incidence and severity of PONV, during the first 24 h after surgery, in 85 Japanese patients receiving intravenous patient-controlled analgesia fentanyl analgesia for postoperative pain control. Eight tag SNPs of the OPRM1 gene (rs1799971, A/G; rs510769, G/A; rs4870266, G/A; rs3798683, G/A; rs1323042, A/C; rs609623, C/T; rs9397685, A/G; and rs644261, C/G) were selected based on their minor allele frequency (>10%) and linkage disequilibrium strength (<80%), and genotyped for haplotype analysis and determination of associations with PONV. Only one out of eight investigated SNPs, rs9397685, in the intronic part of the OPRM1 gene was associated with differences in the occurrence and severity of PONV. We also found four common haplotypes with a frequency of >10% in the investigated patients, including GGGAACAC (33%), AGGGACAC (19%), GGGAACGC (12%), and AGAGACAC (10%). The severity of PONV in carriers of the GGGAACGC haplotype was significantly lower than in the carriers of the other haplotypes (P < 0.05). One intronic SNP, rs9397685, and haplotypes constructed from eight SNPs within the OPRM1 gene locus might be involved in the severity of PONV associated with general anesthesia and opioid administration. This novel finding, if validated and verified in larger and additional ethnic cohorts, might contribute to better knowledge of the contribution of the OPRM1 gene to PONV.

Medicines reclassification from a pharmaceutical industry perspective: An international qualitative study.

BACKGROUND: Widening access to medicines through reclassification ('switching') of medicines from prescription to non-prescription is an international trend generally welcomed by community pharmacists. Research has focused on scheduling and committee deliberations affecting reclassification, rather than industry aspects, despite industry's role in driving reclassifications. The research aimed to identify how pharmaceutical industry and product-related factors influence reclassification, and to explore stakeholder acceptability of government or third-party driven reclassifications. METHODS: Sixty-five in-depth, semi-structured interviews were conducted with 80 key informants (including representatives from regulatory bodies, industry, pharmacy and medicine) in developed countries including the United States, the United Kingdom, Japan, Australia, and New Zealand. The questions explored barriers and enablers to reclassification at the local (micro-), regional (meso-) and global (macro-) levels. Analysis of transcribed interviews entailed descriptive and thematic approaches. RESULTS: Pharmaceutical industry decisions to drive medicine reclassification reflect characteristics of the company, product, and external environment at all levels. For the company, financial factors, company focus (e.g. on prescription business versus non-prescription business), and capability in non-prescription medicines and reclassification were common influences. Products with significant non-prescription market potential and a well-known prescription medicine brand name most suited reclassification, usually near patent expiry. Barriers included immediate generic entry post-reclassification, and a short-term profitability and/or prescription business focus. Some countries allow government or a third-party (including pharmacy) to drive reclassifications, with examples of successful reclassifications ensuing. Some industry and other participants held concerns about this practice, particularly in the United States. Concerns included insufficient resourcing, and the pharmaceutical company's business, potentially encouraging product withdrawal or legal challenge. CONCLUSIONS: This study is the first to explore both pharmaceutical industry factors affecting reclassification and acceptability of alternate drivers of reclassification. Factors beyond clinical safety and efficacy and the local reclassification environment can influence reclassification. Pharmacy-driven reclassification might be one alternative.

The Effect of Pharmacist-led Psychiatric Pharmacotherapy Conferences on the Appropriate Use of Antipsychotics.

The Hakodate Watanabe Hospital has held pharmacist-led multidisciplinary psychiatric pharmacotherapy conferences since September 2013 in order to optimize pharmacotherapy. The effects of holding regular conferences on the correction of high-dose antipsychotic polypharmacy, prevention and reduction of adverse reactions to antipsychotics, and reduction of the drug costs were investigated in psychiatric inpatients prescribed 4 or more antipsychotics. The results revealed that the number of antipsychotics and number of all drugs were significantly reduced by 1, the chlorpromazine (CP)-equivalent dose was significantly reduced by approximately 350 mg, and the drug costs were significantly reduced by 176.5 yen/d. In regard to the effects on the laboratory test data, the blood glucose and hemoglobin A1c (HbA1c) levels were significantly reduced. In addition, 84.8% of the patients were assessed as "unchanged" using the Clinical Global Impression of Change (CGI-C), indicating the absence of any significant changes in the severity of the clinical psychiatric symptoms. The results confirm that psychiatric pharmacotherapy conferences are effective for promoting appropriate use of antipsychotics, reducing the incidence of metabolic adverse reactions, such as elevation of the blood glucose, and also reducing the drug costs. The above results suggest that psychiatric pharmacotherapy conferences encourage psychiatric medical teams to adjust prescriptions while sharing information, and are effective for optimizing pharmacotherapy.

Haplotype analysis of UDP-glucuronocyltransferase 2B7 gene (UGT2B7) polymorphisms in healthy Japanese subjects.

OBJECTIVES: UDP-glucuronocyltransferase 2B7 (UGT2B7) catalyzes glucuronidation of various types of endogenous compounds and drugs, but the genetic basis of interindividual variation in the metabolism of these substances has not yet been sufficiently elucidated. In addition, information about single nucleotide polymorphisms (SNPs) and haplotypes of the UGT2B7 gene that encode the enzyme in the Japanese population is still far from sufficient. DESIGN AND METHODS: We paid special attention to and performed an investigation on -327A > G, -161T > C, -138G > A, and -125T > C in the proximal promoter region, which is regarded as being important for the transcription of the UGT2B7 gene, and also on 211G > A and 802C > T, i.e., non-synonymous SNPs of exon 1 and exon 2 that encode the substrate binding domain. Their genotypes were determined by PCR-direct sequencing. RESULTS: As a result of genotyping, the minor allele frequencies in 160 Japanese individuals were found to be as follows: -327SNP A allele, 0.244; -161SNP T allele, 0.244; -138SNP A allele, 0; -125SNP C allele, 0.078; 211SNP T allele, 0.148 and 802SNP T allele, 0.244. By computational haplotype analysis, it was found that these regions formed a linkage disequilibrium block, and the presence of five haplotypes was demonstrated. CONCLUSIONS: These results suggest that the haplotype structure in the Japanese population is different from that of other ethnic groups.

[Relationship between dose of mycophenolate mofetil and the occurrence of cytomegalovirus infection and diarrhea in renal transplant recipients].

To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.

Why does increasing public access to medicines differ between countries? Qualitative comparison of nine countries.

OBJECTIVE: To identify factors associated with differences between developed countries in reclassifying (switching) medicines from prescription to non-prescription availability. METHODS: Cross-national qualitative research using a heuristic approach in the US, UK, Japan, Australia and New Zealand, supplemented by data from Canada, Denmark, the Netherlands and Singapore. In-depth interviews with 80 key informants (65 interviews) explored and compared factors in terms of barriers and enablers to reclassification of medicines in each country. Document analysis supplemented interview data. RESULTS: Each country had a unique mix of enablers and barriers to reclassification. Enablers included government policy (particularly in UK), pharmacist-only scheduling (particularly in Australia and New Zealand) and large market size (particularly in the US and Europe). Local barriers included limited market potential in small countries, the cost of a reclassification (particularly in the US), competition from distributors of generic medicines, committee inconsistency and consumer behavior. UK had more enablers than barriers, whereas in Australia the opposite was true. CONCLUSIONS: Different factors limit or enable reclassification, affecting consumer access to medicines in different countries. For countries attempting to reduce barriers to reclassification, solutions may include garnering government support for reclassification, support and flexibility from the medicines regulator, having a pharmacy-only and/or pharmacist-only category, providing market exclusivity, ensuring best practice in pharmacy, and minimizing the cost and delays of reclassification.

Detection of the four sequence variations of MDR1 gene using TaqMan MGB probe based real-time PCR and haplotype analysis in healthy Japanese subjects.

OBJECTIVES: P-glycoprotein (P-gp) is significant from the viewpoint of pharmacokinetics/pharmacodynamics (PK/PD). MDR1 gene encodes P-gp and has a wide variety of SNPs. As the SNPs may be one of the factors that induce pharmacogenetic individual difference, haplotype analysis is necessary to evaluate the PK/PD. DESIGN AND METHODS: The SNPs of the detected MDR1 were -129T>C, 325G>A, 2677G>T/A, and 3435C>T. For the analysis of linkage disequilibrium (LD) and haplotype analysis, and for the reconstruction of the haplotype pair, ARLEQUIN and PHASE were employed. RESULTS: The result of the chi(2) test detected significant LD between -129 and 2677, -129 and 3435, and 2677 and 3435. There were 9 haplotypes: T-G-C, T-T-C, C-T-C, T-A-C, C-A-C, T-G-T, T-T-T, C-G-T, and C-T-T. CONCLUSIONS: LD was found among the positions -129, 2677 and 3435. As a result, 9 haplotypes exists in the Japanese population. These results suggest that it would be necessary to give consideration to haplotype for the purpose of evaluating the PK/PD of the drugs transported by P-gp.

Single-nucleotide polymorphisms and copy number variations of the FCGR2A and FCGR3A genes in healthy Japanese subjects.

FcγRII and FcγRIII are low-affinity Fcγ receptors that are encoded by the FCGR2A and FCGR3A genes, respectively. These genes contain functional single-nucleotide polymorphisms (SNPs), which alter the binding affinities of these receptors for the γ chain of the Fc fragment of immunoglobulin G. The known SNPs in FCGR2A and FCGR3A are rs1801274 (A>G; H131R) and rs396991 (T>G; F158V), respectively. It is also known that there are copy number variations (CNVs) in the genetic locus (1q23) where FCGR2A and FCGR3A are located. However, the frequencies of these SNPs and CNVs have not been determined in the Japanese population. The aim of this study was to investigate SNPs and CNVs in FCGR2A and FCGR3A among 113 healthy individuals. The SNPs and CNVs in FCGR2A and FCGR3A were determined using the TaqMan® SNP Genotyping and the TaqMan® Copy Number assays. Our results revealed that the incidence of FCGR2A (rs1801274) genotypes were as follows: A/A, 69.9%; A/G, 29.2%; and G/G, 0.9%. The incidence of the FCGR3A (rs396991) genotypes were as follows: T/T, 56.7%; T/G, 38.9%; and G/G, 4.4%). No CNVs were detected for FCGR2A. To the best of our knowledge, this finding has not been previously reported in the Japanese population. By contrast, CNVs were observed in FCGR3A (3 subjects were found to harbour a gene deletion and 5 subjects had 3 copies of the gene). Using simple commercially available assays we were able to confirm previous findings regarding FCGR2A and FCGR3A alleles and CNVs. These assays may provide a basis for the investigation of the role of these genes in the efficacy of antibody-based drugs, such as trastuzumab and rituximab, in Japanese subjects.

Widening consumer access to medicines through switching medicines to non-prescription: a six country comparison.

BACKGROUND: Switching or reclassifying medicines with established safety profiles from prescription to non-prescription aims to increase timely consumer access to medicines, reduce under-treatment and enhance self-management. However, risks include suboptimal therapy and adverse effects. With a long-standing government policy supporting switching or reclassifying medicines from prescription to non-prescription, the United Kingdom is believed to lead the world in switch, but evidence for this is inconclusive. Interest in switching medicines for certain long-term conditions has arisen in the United Kingdom, United States, and Europe, but such switches have been contentious. The objective of this study was then to provide a comprehensive comparison of progress in switch for medicines across six developed countries: the United States; the United Kingdom; Australia; Japan; the Netherlands; and New Zealand. METHODS: A list of prescription-to-non-prescription medicine switches was systematically compiled. Three measures were used to compare switch activity across the countries: "progressive" switches from 2003 to 2013 (indicating incremental consumer benefit over current non-prescription medicines); "first-in-world" switches from 2003 to 2013; and switch date comparisons for selected medicines. RESULTS: New Zealand was the most active in progressive switches from 2003 to 2013, with the United Kingdom and Japan not far behind. The United States, Australia and the Netherlands showed the least activity in this period. Few medicines for long-term conditions were switched, even in the United Kingdom and New Zealand where first-in-world switches were most likely. Switch of certain medicines took considerably longer in some countries than others. For example, a consumer in the United Kingdom could self-medicate with a non-sedating antihistamine 19 years earlier than a consumer in the United States. CONCLUSION: Proactivity in medicines switching, most notably in New Zealand and the United Kingdom, questions missed opportunities to enhance consumers' self-management in countries such as the United States.

Association between the low-dose irinotecan regimen-induced occurrence of grade 4 neutropenia and genetic variants of UGT1A1 in patients with gynecological cancers.

The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22-38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.

The association between heterozygosity for UGT1A1*6, UGT1A1*28, and variation in the serum total-bilirubin level in healthy young Japanese adults.

AIMS: Considerable variations in the serum total-bilirubin concentrations are observed in healthy subjects. Both sex and the UGT1A1 homozygous genotypes,*6/*6 and *28/*28, are known to influence this variation. However, currently, there is no consensus on the relationship of the heterozygous genotypes *1/*6, *1/*28, or *6/*28 and interindividual variation in the serum total-bilirubin levels. In the present study, we sought to clarify the involvement of heterozygous alleles *6 and *28 in the interindividual difference in the serum total-bilirubin levels among healthy young Japanese adults. METHODS: We enrolled 92 healthy Japanese aged 20-30 years (37 men and 55 women). The serum total-bilirubin levels were compared between men and women and with different UGT1A1 genotypes. Multiple regression analysis was used to investigate the relationships between individual differences in the serum total-bilirubin levels, UGT1A1 genetic variants, and sex. RESULTS: Serum total-bilirubin levels were significantly lower in women than in men. There were also significant differences in the serum total-bilirubin levels between the *1/*1 and *1/*28 genotype, the *1/*1 and *6/*28 genotype, the *1/*6 and *1/*28 genotype, and also the *1/*6 and *6/*28 genotype. Multiple regression analysis showed significant relationships between the serum total-bilirubin level, the UGT1A1 genotypes *1/*28 and *6/*28, and sex. This model explained 42.3% of the interindividual variation in serum total-bilirubin levels. CONCLUSIONS: We found that the UGT1A1 genotypes *1/*28 and *6/*28 as well as sex contributed to interindividual variations in the serum total-bilirubin levels. In contrast, UGT1A1*1/*6 showed only minimal involvement in individual differences in serum total-bilirubin levels.

Use of psychotropics and the risk of falls in hospitalized psychiatric patients.

As hospitalized patients in psychiatry departments are often prescribed multiple psychotropics depending on their psychiatric symptoms, psychotropics are considered as important factors potentially associated with a high risk of falls. In this study, we attempted to investigate, from the aspect of drug prescription, to what degree the number and doses of psychotropics must be adjusted in order to reduce risk of falls in hospitalized psychiatric patients. The subjects were 526 patients, consisting of a fall group of 313 patients, who had experienced 1 to 5 falls (510 events) and a control group of 213 patients who had never experienced falls. Multiple logistic regression analysis was performed to determine the correlations between the occurrence of falls and the number and doses of psychotropics. The results showed that the risk of falls increased with increasing number of antipsychotics and anxiolytics/hypnotics prescribed, with the risk increasing, by 3.75-fold with the increase in the dose of chlorpromazine (CP)-equivalents to more than 600 mg, by 2.08-fold when the dose of diazepam (DAP)-equivalents to more than 15 mg, and by 7.80-fold with increase in CP-equivalents to more than 600 mg concomitantly with an increase in DAP-equivalents to more than 15 mg. In addition, a tendency towards increase in the frequency of falls was observed when more than 5 psychotropics were prescribed concomitantly. The above results suggested that the risk of falls may be reduced by appropriately adjusting the number of drugs and the doses of psychotropics used in the treatment of psychiatric disorders.